This application relates to nutritional supplement compositions and methods of the use of the nutrition supplements to maximally stimulte contraction of the gallbladder in patients undergoing rapid weight loss, for the purpose of preventing the build up of bilary sludge and/or gallstones.
Gallbladder disease is widespread and occurs in an estimated 20 million Americans, with over 2.5 billion dollars spent annually on surgical interventions. The etiology of gallbladder disease is complex and incompletely understood. Several key factors appear to interact for gallstone formation including obesity, biliary stasis, biliary lithogenicity and nucleation of bile solutes. The prevention or mitigation of all, or several of these factors may be helpful in minimizing the need for surgery and decrease the incidence and severity of this national health issue.
Recent clinical trials have evaluated several different preventative treatments including oral chemolysis with ursodiol, which decreases the lithogenicity of the bile; cholecystokinin infusion, which decreases stasis in long-term total parenteral nutrition patients (TPN); and aspirin or anti-inflammatory drugs, which appear to decrease nucleation factors. These approaches each have shown a significant impact in decreasing the incidence of sludge as well as stone formation. Other clinical studies, have shown the development of small cholesterol gallstones in some obese patients undergoing rapid weight loss. These findings were associated with favorable conditions for gallstone formation: an increase in cholesterol saturation, an increase in nucleation factors, and an increase in biliary sludge. The increase in biliary sludge has also been reported consistently in TPN patients prior to the development of gallstones.
One logical strategy for minimizing sludge development is frequent stimulation of gallbladder contraction in order to minimize gallbladder stasis. It is hypothesized that this event may override the importance of the other key factors needed for stone formation and that frequent contraction may prevent the build up of sludge in the gallbladder, at least during periods of caloric restriction. Since gallbladder contraction is under hormonal, as well as vagal control, and since the hormonal control is regulated significantly by diet, it would seem justified to investigate the use of dietary formulations that would contract the gallbladder maximally and frequently for the purpose of preventing build up of biliary sludge.
The exact pathogenesis of cholesterol gallstone development remains unresolved. It is hypothesized that several key factors are essential for the ultimate formation of the stones. Lithogenic bile, saturated with either cholesterol or calcium bilirubinate is an important prerequisite. Once the concentration of either critical compound has exceeded its ability to be solubilized by the biliary phospholipids and bile acids, precipitation or crystallization may occur. However, cholesterol supersaturation of bile alone does not necessarily lead to gallstone formation. A second critical factor for stone development is the nucleation of bile solutes which allows these key compounds, cholesterol or calcium bilirubinate, to crystalize or granulize within the gallbladder. The secretion of mucus glycoproteins by the gallbladder epithelium has been reported to play a pivotal role in the initiation of this process. It has been suggested that these nucleation factors appear to be influenced by the concentration of arachiodonic acid in the biliary phospholipid matrix, by the concentration of deoxycholic acid as well as by the eiconsanoids derived from omega-6 fatty acids. A third critical element is gallbladder stasis. It is hypothesized that the stasis may allow the other important factors, lithogenicity and nucleation, the opportunity to initiate microcrystals in the sludge and set the ground work for continued stone growth. Recent clinical trials have suggested that the prevention of this final key element may be powerful enough to minimize the importance of the prior two key factors. However, no totally conclusive data are present in the literature citing defective gallbladder motor function creating biliary stasis as the critical factor in patients that have gallstones. In fact, data have been reported that gallstone patients have increased, dedreased or no change in motor function when compared to control subjects.
A very critical factor in the development of gallstones, that lends itself to be influenced by dietary factors, is inadequate gallbladder contraction and biliary stasis. The contraction and subsequent emptying of the gallbladder is under both vagal and hormonal control. Truncal vagotomy has been shown to significantly improve the composition of biliary lipids and bile acid pool sizes, suggesting that vagal tone does little to contribute to gallstone predisposition by changing the CSI. Further studies on the effect of cholinergic changes on gallbladder emptying have shown the CCK-stimulated gallbladder emptying was increased in patients whicfh had undergone vagotomy as compared to non-vagotomized control patients.
However, the effects of vagotomy on gallbladder motor function are still controversial since some investigations report a decrease or no effect of cholinergic disruption in gallbladder emptying. The gastrointestinal hormone, cholecystokinin (CCK), then becomes a very important modulator of gallbladder contraction and emptying. The release of this hormone can be significantly stimulated by specific dietary nutrients, in particular dietary protein (animo acids and or peptides) and/or fat. The quantity of CCK that is released directly correlates with the degree of gallbladder contraction. It is hypothesized that the greater the degree of gallbladder contraction with a single meal stimulus, the better the chance to minimize the impact of gallbladder stasis.
The importance of gallbladder stasis in the development of gallstones has been described by a number of investigators. The prevention of gallbladder stasis, in the cholesterol-fed prairie dog model, various methods including sphincterotomy, a protein-fat nasal infusion, or else by daily CCK injection have all been shown to prevent gallstone formation. In the latter study, all patients on TPN therapy developed sludge after six weeks of treatment. However, the oral refeeding of these patients over a four week period completely eliminated all the biliary sludge detectable by ultrasonography. The former trial randomized previously treated TPN patients with no gallbladder sludge or stones into two groups; one group received a daily infusion of CCK while the second group received a daily infusion of saline. After an unspecified period of CCK or saline infusion, none of the patients treated with CCK developed any detectable sludge or stones while five out of eight patients treated with saline had developed biliary sludge. Unfortunately, neither CSI or the nucleation times were measured in this study so that it is not certain how these key factors may have been influenced by frequent gallbladder contraction.
During low calorie dieting for substantial weight loss, resultant poor stimulation of gallbladder emptying because of inadequate fat and/or protein to stimulate CCK release might facilitate cholesterol nucleation, gallbladder sludge formation and/or stone growth and retention with subsequent increased rate of gallstone formation. This is an especially important concept since an increase in biliary cholesterol saturation index has not been consistently reported to occur in obese subjects during rapid weight loss. However, a recent abstract in which the gallbladders of weight-reducing obese patients were contracted by CCK infusion every three to seven days for 28 days reported that the CSI and nucleation time did not change significantly over time and the bile became more lithogenic. However, this study did not measure fasting or residual gallbladder volume so it is not certain if gallbladder contraction changed over time.
There is conflicting data in the literature regarding the effect of obesity on gallbladder motility. it has been shown in obese diabetic and non-diabetic patients that there was no correlation between the degree of obesity and gallbladder emptying in response to cholecystokinin. These results also suggest that obese subjects do not have a impaired CCK release in response to a maximal liquid meal stimulus. These data do conflict with other data where it is reported larger gallbladder volumes in obese subjects and a reduced percent gallbladder emptying in response to a solid meal stimulus when compared to normal weight subjects. However, gallbladder volumes in both normal weight and obese subjects in this latter study were greater than two times the values found in the previous study, and substantially higher than the majority of published values. Differences in percent emptying between the two studies may relate to differences in the nature of the emptying stimuli (solid complex meal versus CCK infusion) or to the delivery of the stimulus to the duodenum mediated by the rate of gastric emptying.
Thus, there is a need to find a way, such as via a nutritional formulation, to maximally contract the gallbladder on a daily basis in obese patients undergoing caloric restriction for weight loss to prevent or mitigate the formation of gallstones. All weight reducing diets or calorically restricted diets at present, attempt to significantly decrease the amount of dietary fat consumed per day by the patient undergoing therapy. Excessive intake of dietary fat and total calories is considered by most health professionals to be the major nutrient imbalance in our diet that precipitates the disease of obesity. As a result of this concern, the health professionals attempt to restrict the amount of dietary fat consumed daily and also the amount of dietary fat consumed at any one eating occasion. In fact, most diet phases drastically reduce the amount of dietary fat consumed at a very important meal, breakfast, by encouraging the use of cereal on grain products with skim milk. The gallbladder is distended maximally or contains the greatest volume of bile in the morning after an overnight fast. Furthermore, the gallbladder empties to the greatest extend when contracted maximally in the morning. Thus, it becomes very important to contract the gallbladder maximally in the morning and to use a nutritional composition, in the reduced calorie diet plan, that contains a significant quantity of dietary fat and protein. It can be seen from the previous review, that the obese patient undergoing weight reduction could be at an increased risk of developing gallbladder abnormalities (sludge or stress) if the gallbladder is not effectively evacuated or contracted on a daily basis. Thus, the nutritional compostion of the reduced calorie diet plus the time at which the food is consumed, could be an important concept that has not been fully appreciated in mitigating gallbladde disease.